Taking prednisone 60 mg for a week for myasthenia gravis.Reappraisal of Oral Steroid Therapy for Myasthenia Gravis
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Taking prednisone 60 mg for a week for myasthenia gravis. A Practical Approach to Chronic Immunosuppression in Myasthenia Gravis |
Taking prednisone 60 mg for a week for myasthenia gravis.
Frontiers | Reappraisal of Oral Steroid Therapy for Myasthenia Gravis - REVIEW article
A Practical Approach to Chronic Immunosuppression in Myasthenia Gravis
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All rights reserved. A practical approach to initiating and tapering corticosteroids, and the considerations in the selection and monitoring parameters of steroid-sparing agents are crucial to the care of myasthenia gravis. Chronic immunosuppression is among the mainstays of long-term therapy in MG. This article offers a practical approach to initiating and tapering corticosteroids, in addition to reviewing some of the considerations in the selection and monitoring parameters of steroid-sparing agents.
We will also briefly introduce some novel therapies for MG. Per international consensus, corticosteroids specifically prednisone comprise first-line immunosuppressive therapy for all patients who have not achieved disease control with pyridostigmine. The low-dose, slow-titration approach is generally appropriate for patients with mild-to-moderate generalized or ocular disease. This regimen is less likely to produce the paradoxical worsening that can be seen within the first 3 weeks in up to half of patients started on steroids.
The high-dose treatment regimen involves initiation of prednisone at a dose of 1. The high daily dosing or alternate-day dosing is maintained until a plateau has been reached in clinical improvement for at least 4 weeks. Once the patient is on 20 mg daily, tapering is commonly slowed to decrease by increments of 5 mg every month. Below 10 mg daily, an even slower taper 1. The low-dose, slow-titration schedule starts the patient on 10 to 20 mg of prednisone per day, with an increase of 10 mg every 1 to 2 weeks up to 1 to 1.
If a patient experiences relapse in symptoms during a taper, the dose of steroids is increased again to the lowest effective dose. Chronic, continual corticosteroid use is associated with increased susceptibility to infection, diabetes, weight gain, osteoporosis, steroid myopathy and aseptic necrosis of the joints. Monitoring of bone density with a dual-energy X-ray absorptiometry DEXA scan at baseline and at 6 to 12 months after steroid initiation can be considered, and patients should be prophylactically started on calcium and vitamin D supplements to prevent osteoporosis.
Blood glucose should also be monitored carefully while patients are maintained on steroids, particularly when they are on higher doses. Due to the myriad of complications that result from chronic corticosteroid use, the objective is to taper patients down to the lowest effective steroid dose without causing recurrence of symptoms. They may be started simultaneously with prednisone in patients with severe disease due to their delay in onset of action; they can also be started later on if a patient is unable to taper to low-dose prednisone often accepted to be 10 mg or less daily without relapsing.
Once a patient has remained stable for 6 to 12 months on a steroid-sparing agent, prednisone can be gradually tapered as previously described. Various classes of steroid-sparing immunosuppressants are used to treat MG: antimetabolites eg, azathioprine, mycophenolate mofetil, methotrexatecalcineurin inhibitors eg, cyclosporinemonoclonal antibodies eg, rituximabcomplement inhibitors eg, eculizumab, ravulizumaband the upcoming FcRn antagonists.
Azathioprine is the most frequently utilized steroid-sparing immunosuppressant in MG and currently has the best efficacy data. Complications can include bone marrow suppression, hepatic toxicity, pancreatitis, and teratogenicity. Screening for deficiency of the enzyme thiopurine methyltransferase, which predisposes patients to bone marrow toxicity in those exposed to azathioprine, is often performed, although the benefit is unclear.
Leukopenia is a good indicator of bone marrow suppression, and it can be seen as early as 1 to 2 weeks after initiation. Its ease of use and tolerability are also attractive. Clinical improvement is most often observed within the first 3 months but can be delayed up to 1 year after initiation. A CBC should be obtained at baseline and then closely monitored. MMF is teratogenic and contraindicated in pregnancy.
Evidence for the benefit of methotrexate MTX in MG is limited, but it may be considered for patients who have not responded to other steroid-sparing agents. It is started at 7. Due to teratogenicity, MTX is contraindicated in women who may become pregnant; it should also be used in caution with patients with lung disease. Cyclosporine has been shown to be effective in the treatment of MG but is rarely chosen as a first-line agent due to its AE profile and monitoring parameters.
Its main advantage over azathioprine is its quicker onset of action, with improvement typically seen within 2 to 3 months of initiation.
Trough cyclosporine levels should also be monitored. Other AEs include hypertension, tremor, liver toxicity, hirsutism, paresthesias, and headache. Before initiating rituximab, patients should obtain a baseline CBC and be screened for hepatitis B due to the risk of reactivation.
Possible AEs also include leukopenia, anemia, and thrombocytopenia. An uncommon but potential complication is the development of progressive multifocal encephalopathy. Complement inhibitors interfere with the autoimmune pathway, which results in endplate destruction. Zilucoplan is a synthetic peptide that binds to complement protein C5 at a different binding site compared with eculizumab, so it may be considered in the future for patients with C5 mutations who do not respond to eculizumab.
Ravulizumab is a monoclonal humanized antibody that also binds to complement protein C5 but has a longer half-life compared with eculizumab and can be administered every 8 weeks. The FcRN antagonists comprise a novel class of medications in the treatment of MG; they aim to interfere with the recycling of autoantibodies in the process of lysosomal degradation. Rozanolixizumab is a humanized IgG4 monoclonal antibody that was given as a subcutaneous infusion once weekly for 6 weeks in a randomized, subject-blind, placebo-controlled trial in patients with anti-AChR MG.
The study demonstrated improvement in all clinical scores compared with placebo without reaching statistical significance, but improvement in the MG-Activities of Daily Living score was statistically higher in the treatment arm compared with placebo. Chronic immunosuppressive therapy in MG can provide long-term stability for many patients. For patients who continue to be refractory or are unable to tolerate current medication options due to AEs, emerging novel therapies with more targeted immunosuppression may offer alternatives in the near future.
Video Series. December 24, NeurologyLiveDecemberVolume 4, Issue 7. Corticosteroids Per international consensus, corticosteroids specifically prednisone comprise first-line immunosuppressive therapy for all patients who have not achieved disease control with pyridostigmine.
Steroid-Sparing Agents Various classes of steroid-sparing immunosuppressants are used to treat MG: antimetabolites eg, azathioprine, mycophenolate mofetil, methotrexatecalcineurin inhibitors eg, cyclosporinemonoclonal antibodies eg, rituximabcomplement inhibitors eg, eculizumab, ravulizumaband the upcoming FcRn antagonists.
Antimetabolites Azathioprine is the most frequently utilized steroid-sparing immunosuppressant in MG and currently has the best efficacy data. Calcineurin Inhibitors Cyclosporine has been shown to be effective in the treatment of MG but is rarely chosen as a first-line agent due to its AE profile and monitoring parameters. FcRN Antagonists The FcRN antagonists comprise a novel class of medications in the treatment of MG; they aim to interfere with the recycling of autoantibodies in the process of lysosomal degradation.
International consensus guidance for management of myasthenia gravis: executive summary. Neuromuscular Disorders. McGraw-Hill Medical; Treatment of myasthenia gravis. Neurol Clin. Update in immunosuppressive therapy of myasthenia gravis. Autoimmune Rev. International consensus guidance for management of myasthenia gravis: update. Safety, efficacy, and tolerability of efgartigimod in patients with generalised myasthenia gravis ADAPT : a multicentre, randomised, placebo-controlled, phase 3 trial.
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The maximum prednisone dose ranged from mg. Tapering to ≤10mg per day required ≤4 months for all but two patients. Median average daily. In the s and s, many clinicians preferred to start prednisone at a low dose (10–25 mg) gradually increasing to 60– mg on alternate. The maximum prednisone dose ranged from mg. Tapering to ≤10mg per day required ≤4 months for all but two patients. Median average daily. MYASTHENIA GRAVIS (MG) IS AN autoimmune disorder caused by the the first 3 weeks in up to half of patients started on steroids.2,3 The. Another study started prednisolone at 10 mg/day for 2 days, followed by 20 mg/day for 2 days, then the dose was increased to 50–60 mg/day for 1. Many patients and physicians prefer to taper corticosteroid doses by combining with other immunosuppressive agents to reduce the side effects of long-term monotherapy with high-dose oral corticosteroids, including mood symptoms and cosmetic problems 33 — Lifetime course of myasthenia gravis. Ann N Y Acad Sci. Table 2.Treatment with oral corticosteroids at high doses with an escalation and de-escalation schedule is effective against myasthena gravis MG. However, long-term use of oral steroids above a certain dosage level is known to cause a number of problems. In , a multicenter, cross-sectional study revealed that higher PSL dose and longer PSL treatment do not ensure better outcome. In , we conducted a multicenter, cross-sectional study in a large population of Japanese patients with generalized MG, aiming to elucidate the correlation between oral PSL regimens and achievement of treatment goals.
The ORs for low vs. Early combination with fast-acting therapy OR 2. These results indicate that early combination of low-dose PSL regimens with other therapies is the key for early achievement of treatment goals in generalized MG. These results suggest the limitation of the current oral corticosteroid therapy. We need to develop new treatment options to increase the rate of satisfactory outcome. Oral corticosteroids remain the primary treatment for generalized myasthenia gravis MG , although various other disease-modifying therapies have emerged 1.
Primary disease-modifying therapies for MG include immunosuppression therapy using oral prednisolone PSL , azathioprine, cyclosporine, mycophenolate mofetil, and tacrolimus 2 — 6. Methotrexate, another immunosuppressant, is an effective steroid-sparing agent having similar efficacy and tolerability to azathioprine 7.
For patients receiving low-dose prednisolone, treatment goal is usually set at minimal symptoms MM according to the Myasthenia Gravis Foundation of America MGFA postintervention status To achieve the treatment goal, various immunosuppressive agents have been added to corticosteroids as steroid-sparing agents at the start of treatment 5 , 15 — This short review will provide an overview of corticosteroid treatment for generalized MG, and introduce a favorable regimen of oral corticosteroids for generalized MG based on a nationwide survey in Japan.
In , Simon 19 reported the effects of treating MG with anterior pituitary extract. This was probably the first description of the therapeutic effect of corticosteroid-related agents on MG.
Subsequently, many reports of small-scale studies in the s and s described favorable effects of adrenocorticotropic hormone and corticosteroids on MG. Grob et al. Prednisone and prednisolone are the oral corticosteroids commonly used for MG treatment.
Both are synthetic corticosteroids sharing similar pharmacological properties such as effectiveness, adverse side effects, dosing schedules, and drug interactions. Prednisone is a biologically inactive compound which must be converted by liver enzymes to prednisolone before it can act.
Therefore, it is prudent to use prednisolone that do not require enzymatic activation in clinical settings in which liver enzymatic activity is impaired such as severe hepatic failure In , Warmolts et al. Pascuzzi et al. They reported that sustained improvement was achieved after a mean of Finally, they found Sghirlanzoni et al.
In addition, they found the best results in those whose symptoms started after the age of 40 years, and a correlation between the starting dose of prednisone and the rate of improvement. On the other hand, Bae et al. They noted the possibility of steroid-induced exacerbation when prescribing prednisone for MG, especially when treating elderly patients and patients with bulbar dominant or severe disease.
Although there are few randomized trials of oral corticosteroids alone, a Cochrane systematic review on corticosteroids for MG published in concluded that limited evidence from randomized controlled trials does not show any difference in efficacy between corticosteroids and either azathioprine or intravenous immunoglobulin Dose escalation and de-escalation was also performed traditionally in Japan. Treatment was continued at the highest dose followed by gradual tapering, although the oral steroids usually had to be given chronically with significant risk of adverse events.
To address the difficulty of achieving complete remission in adult-onset generalized MG cases, the Japanese clinical guidelines for MG published in recommend that treatment strategies should aim to maintain health-related quality of life and mental health, considering the possibility of prolonged treatment The guidelines also recommend to reconsider the use of high-dose steroids with escalation and de-escalation, in view of the problems associated with long-term use and the availability of other treatment options.
The expected pharmacologic actions of corticosteroids for treating MG may be divided into an anti-inflammatory action and an immunosuppressive action. Corticosteroids target the postsynaptic membrane to suppress inflammatory reactions including complement-mediated reactions at the endplates. The corticosteroids also inhibit the immune system at multiple sites, including sequestration and decrease of lymphoid cells The anti-inflammatory and immunosuppressive actions of corticosteroids are inextricably linked, perhaps because they both involve inhibition of leukocyte functions In pharmacokinetics, glucocorticoids GC , a class of corticosteroids, diffuse across cell membrane and bind to cytoplasmic GC receptor GR.
This binding leads to dissociation of heat shock protein 90, and induces transport of the GC-GR complex across nuclear membrane to the nucleus. In the nucleus, the GC-GR complex binds with various genetic promoters and enhancers of genomic DNA according to the GC responsive elements to regulate the transcription of the target genes Indeed, it is known that high doses of GCs inhibit immunoglobulin synthesis, kill B cells 30 , and decrease production of components of the complement system Then, the clinical question is: Does higher doses of corticosteroids ensure better outcome in MG treatment?
As described in the history of MG therapy, oral corticosteroids are traditionally used at high doses with escalation and de-escalation schedules. High-dose oral steroids may not always provide sufficient improvement and may induce long-term steroid-related side effects that impair the quality of life QOL of many patients 5 , We studied MG patients in to investigate the relationship between oral prednisolone PSL dosage and the status of disease at the time of study current status The treatment duration with PSL was also similar in the two groups 6.
The daily dose of PSL was significantly lower in the MM or better group than in the improved or worse group 4. In addition, cumulative PSL doses received in the past year was smaller in the MM or better group than in the improved or worse group Figure 1. Classification of MG patients treated with prednisolone according to the present disease status in a multicenter, cross-sectional study in This figure is drawn from data published in Other significant variables identified in univariate analyses and entered into the logistic regression model, including the worst QMG score, PSL dose and duration, and use of calcineurin inhibitors CNI , were not significant independent predictors for the achievement of current status of MM or better.
Table 1. Positive and negative predictors for MM or better status from multivariate logistic regression modeling. These findings lead to the conclusion that higher doses of PSL and longer duration of PSL treatment are not associated with improvement of current condition and that response to PSL treatment is independent of baseline disease severity based on MGFA classification.
In other words, MG patients do not possess specific clinical factors associated with poor response to oral corticosteroids, but they are composed of patients who respond well and others who response poorly to oral corticosteroids. However, according to our results, even in the absence of a crisis or exacerbation, fast-acting treatment may be recommended to induce MM or better status at peak doses of oral PSL. Many patients and physicians prefer to taper corticosteroid doses by combining with other immunosuppressive agents to reduce the side effects of long-term monotherapy with high-dose oral corticosteroids, including mood symptoms and cosmetic problems 33 — We found that in Japan, percentage of CNI use was high in both the MM or better group and the improved or worse group CNIs such as cyclosporine and tacrolimus are recognized as potent corticosteroid-sparing agents, especially in patients receiving high-dose oral corticosteroids for extended periods of time 4 , 36 — If the patients in this study had not been taking CNIs, they may have had to take higher doses of corticosteroids.
We proposed a low-dose regimen of oral corticosteroid treatment in MG based on the results of our nationwide survey in 32 Figure 2. The low-dose regimen includes low dose of oral corticosteroids, early combination of CNIs, and fast-acting treatments to improve remaining symptoms quickly. The next clinical question is: Is the low-dose regimen superior to the high-dose regimen for long-term prognosis of MG? Figure 2. Changes of therapeutic strategy. A The traditional strategy with high-dose oral corticosteroids with escalation and de-escalation schedule.
B The new strategy with low-dose oral corticosteroids. Even the international consensus guidance does not include an internationally accepted standard dosing regimen for oral corticosteroids We conducted a multicenter cross-sectional study to examine the correlation between oral PSL administration method and actual achievement of treatment goals Clinical characteristics, history of non-PSL treatment, and prognosis were compared among the three groups.
The effect of oral PSL regimen on the achievement of treatment goals was followed over a 3-year treatment period. Figure 3. Classification of prednisolone-treated generalized MG patients according to the present disease status in a multicenter, cross-sectional study in ORs for low-dose vs.
These results suggest that early combination of low-dose PSL regimens with other therapies is useful for early achievement of treatment goals in patients with generalized MG. However, only These results suggest the limitations of current oral corticosteroid therapy and the need to improve the safety and efficacy of corticosteroid therapy.
Table 2. Table 3. Oral corticosteroids may be effective for good responders regardless of dosage. MG patients who respond well for various reasons may be able to reduce the dosage of steroids with less difficulty because dose reduction may follow the achievement of good outcome but not cause the outcome.
Moreover, it is not necessary to use high dosage of oral corticosteroids because a number of new treatment options are now available to achieve good outcome.
It is time to reconsider high-dose steroid treatment for MG and seek a novel strategy based on patients' QOL. On the other hand, fast-acting treatment for generalized MG is not suitable for all patients from different countries, especially for patients in developing countries.
In this case, further development of steroid drugs is required. Over the past few decades, considerable efforts have been devoted to increase the potency of corticosteroids while minimizing their side effects by modifying the chemical structure of natural GCs Alternative splicing, alternative translation initiation of mature mRNAs, and post-translational modifications have generated multiple GR isoforms with unique expression, gene regulation, and functional profiles, which have advanced our understanding of the molecular basis of GC susceptibility diversity.
Genome-wide GR recruitment studies have shown significant difference of tissue-specific chromatin landscape in GC susceptibility An important challenge in the clinical application of GC is the heterogeneity of GC response between individuals.
Advances in our understanding of GC expression patterns may reveal important mechanisms of poor response in MG treatment. The breakthrough may accelerate not only the design of novel therapeutic strategies for poor responders but also the prediction of enhanced response to corticosteroids for good responders.
All authors were involved in conception and design of the work, and in acquisition of data. TI was involved in analysis, interpretation of data, and drafted the article. All other co-authors revised it critically for important intellectual content. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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